tbuckley/cabot-search huggingface dataset:
177Lu-DOTA-TLX591 safety, biodistribution and dosimetry study (ProstACT-SELECT).
Authors: Paola Antonini, Danielle Meyrick, Colin Hayward
Journal: Journal of Clinical Oncology (2022)

TPS5109 Background: The cell surface glycoprotein prostate-specific membrane antigen (PSMA) has proven to be an ideal therapeutic target in prostate cancer (PC) as it is highly expressed by malignant prostate cells.1,2 177Lu-DOTA-HuJ591-CHO (TLX591) is a radioimmunoconjugate comprised of the humanized IgG1 mAb rosopatamab, linked to the low energy beta-emitting radioisotope lutetium-177 (177Lu) via the bifunctional chelating agent DOTA-NHS ester. Chinese Hamster Ovary (CHO) cell line has been selected for the manufacture of the recombinant mAb. There is a strong rationale for investigation of TLX591 as a potential radioligand therapy for the treatment of PC, supported by previous clinical evidence of the safety of the antibody, as unconjugated and as a DOTA conjugate, and of the specificity of the antibody for PC tumors. 3,4,5,6. This multicenter Phase 1 radiomics study (ClinicalTrials.gov Identifier: NCT04786847) is designed to evaluate the safety, tolerability, biodistribution and dosimetry of TLX591 administered with best SoC to patients with PSMA-expressing, metastatic castration-resistant prostate cancer (mCRPC) progressing despite prior treatment with a novel androgen axis drug (NAAD). At the time of this abstract the study has commenced recruitment in Australia. This trial is sponsored by Telix Pharmaceuticals. Methods: The study will consist of 2 cohorts: Cohort 1: Five patients will be recruited for evaluation of biodistribution of TLX591 administered in combination with SoC. These patients will receive a single tracer (27 mCi) intravenous (IV) infusion of TLX591, and SPECT images and pharmacokinetic blood samples acquired at several time points until Day 13. A qualitative comparison of biodistribution of tracer level TLX591, as demonstrated by SPECT, with 68Ga-PSMA-11 on PET imaging will be performed to ensure equivalent (or improved) radiopharmaceutical tumour targeting. Dosimetry analysis will also be performed. If safety is confirmed by independent DSMB review, each individual patient in Cohort 1 will proceed 14 days following the initial tracer dose to a second administration of TLX591. SoC therapy will continue according to standard practice. Cohort 2: All further enrolled patients will receive two administrations of 76 mCi TLX591 for further evaluation of safety, tolerability and biodistribution, and efficacy in combination with SoC. 1. Pan M-H et al. 2009 2. Dorff TB et al., 2019 3. Tagawa, Milowsky et al., 2013 4. Tagawa et al., 2019 5. Tagawa, Whang et al., 2014 6. Niaz et al., 2020. Clinical trial information: NCT04786847.
Barriers to and Disparities in Access to Health Care Among Adults Aged ≥18 Years with Epilepsy — United States, 2015 and 2017
Authors: Niu Tian, Rosemarie Kobau, Matthew M. Zack, Kurt J. Greenlund
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Approximately 3 million U.S. adults have active epilepsy (i.e., self-reported doctor-diagnosed history of epilepsy and currently taking epilepsy medication or have had at least one seizure in the past year, or both) (1). One of the most common brain disorders, epilepsy poses a number of challenges for people living with this condition because its treatment can be complex, daily management might be inadequate to achieve seizure control, it limits social participation, and epilepsy is associated with early mortality.† Previous studies indicate that persons with epilepsy are more likely to experience barriers or delays in receipt of certain types of care, including epilepsy specialty care, and that these delays are often associated with individual factors (e.g., seizure type) or social determinants of health (e.g., household income or provider availability) (2-4). To obtain updated estimates of access to health care among U.S. adults aged ≥18 years by epilepsy status, CDC analyzed pooled data from the 2015 and 2017 National Health Interview Survey (NHIS), the most recent years with available epilepsy data. Age-adjusted analyses comparing adults with active epilepsy or inactive epilepsy (i.e., self-reported doctor-diagnosed epilepsy but not currently taking medication for epilepsy and have had no seizure in the past year) with adults without epilepsy indicated that adults with active or inactive epilepsy were more likely to have Medicaid or other public insurance coverage and to report an inability to afford prescription medicine, specialty care, or vision or dental care. Adults with active or inactive epilepsy were more likely to take less medication than prescribed to save money, to be in families having problems paying medical bills, and to report delaying care because of insufficient transportation. Enhancing linkages between clinical and community programs and services by public health practitioners and epilepsy health and social service providers can address gaps in access to health care.
NLRP3 licenses NLRP11 for inflammasome activation in human macrophages
Authors: Anu Gangopadhyay, Savita Devi, Shivendra Tenguria, Jessica Carriere, Huyen Nguyen, Elisabeth Jäger, Hemisha Khatri, Lan H. Chu, Rojo A. Ratsimandresy, Andrea Dorfleutner, Christian Stehlik
Journal: Nature Immunology (2022)

Abstract Intracellular sensing of stress and danger signals initiates inflammatory innate immune responses by triggering inflammasome assembly, caspase-1 activation and pyroptotic cell death as well as the release of interleukin 1β (IL-1β), IL-18 and danger signals. NLRP3 broadly senses infectious patterns and sterile danger signals, resulting in the tightly coordinated and regulated assembly of the NLRP3 inflammasome, but the precise mechanisms are incompletely understood. Here, we identified NLRP11 as an essential component of the NLRP3 inflammasome in human macrophages. NLRP11 interacted with NLRP3 and ASC, and deletion of NLRP11 specifically prevented NLRP3 inflammasome activation by preventing inflammasome assembly, NLRP3 and ASC polymerization, caspase-1 activation, pyroptosis and cytokine release but did not affect other inflammasomes. Restored expression of NLRP11, but not NLRP11 lacking the PYRIN domain (PYD), restored inflammasome activation. NLRP11 was also necessary for inflammasome responses driven by NLRP3 mutations that cause cryopyrin-associated periodic syndrome (CAPS). Because NLRP11 is not expressed in mice, our observations emphasize the specific complexity of inflammasome regulation in humans.
DIPG-23. Artificial intelligence for detecting ACVR1 mutations in patients with DIPG using MRI and clinical data
Authors: Fahad Khalid, Thibault Escobar, Jessica Goya-Outi, Vincent Frouin, Nathalie Boddaert, Jacques Grill, Frederique Frouin
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: ACVR1 mutations are found in about 25% of patients with diffuse intrinsic pontine glioma (DIPG). Recent work has identified the combination of vandetanib and everolimus as a promising therapeutic approach for these patients. We investigate the predictive power of an AI model integrating clinical and radiomic information to predict ACVR1 mutation. METHODS: This retrospective monocentric study includes 65 patients with known ACVR1 status. Patients were scanned at the diagnosis time with at least one of the four structural MRI modalities (pre- and post-contrast T1, T2, FLAIR) and basic clinical information (age and sex) was collected. Radiomic features were extracted within the tumor region from each modality. For each modality, a recursive feature elimination method was used to select the most relevant features. Inside a leave-one-out framework, up to five logistic regression models were built: one per MRI modality and one for the clinical information. The final prediction for each patient was computed as the mean of the probabilities of ACVR1 mutation for the up to 5 different models. Assigning a different weight to clinical data according to age, (more or less than 10 years old) was also tested. RESULTS: Out of the 65 patients (mean age 7.9±3.7, 15 patients older then 10 years), ACVR1 mutations were identified with a 78% accuracy (sensitivity = 92% and specificity = 75%) in the leave-out-out process. Accounting for the clinical data in the model increase the accuracy to 82% (resp. sensitivity = 86% and specificity = 80%). CONCLUSION: The proposed multi model approach compensates for missing MR modalities while taking advantage of all the available information. Our first results suggest that a dedicated model could be developed for younger patients to improve the prediction. The different models will now be tested using additional data coming from the ongoing multi-centric BIOMEDE trials.
Financial toxicity in Hispanic cancer survivors: A nationally representative pancancer analysis.
Authors: Nishwant Swami, Edward Christopher Dee, Brandon A Mahal, Fumiko Chino, Narjust Duma
Journal: Journal of Clinical Oncology (2022)

6528 Background: A cancer diagnosis can pose a significant financial burden to patients and their families, both during and after treatment. Financial toxicity has long-term consequences, with cancer being the most commonly cited reason for medical cost-associated bankruptcy in the United States. We used nationally representative survey data to assess financial toxicity in cancer survivors, with a focus on Hispanic patients given known disparities in socioeconomic and cancer outcomes. Methods: 2013-2018 data from the National Health Interview Survey (NHIS) was used to select individuals aged 18 years old and older who reported any previous diagnosis of cancer. Financial toxicity was defined as unmet healthcare need, health care unaffordability, and/or general financial stress. Individuals were disaggregated by race/ethnicity, and patients who self-identified as Hispanic were further classified by country of origin. Survey-adjusted percentages characterize the cohort. Multivariable logistic regression generated adjusted odds ratios (aORs) with 95% CI for each category of financial toxicity, with non-Hispanic White (NHW) used as reference. Results: Hispanic patients in aggregate had the highest prevalence of all 3 categories of financial toxicity when compared to other racial/ethnicity groups (35% unmet healthcare need, 61% healthcare unaffordability, 61% financial stress). Mexican (aOR: 2.53 95%CI: 1.82–3.52), Cuban/Cuban-American (aOR: 1.97 95%CI: 1.17–3.34), and patients of Central/South American heritage (aOR: 2.61 95%CI: 1.67–4.10) were more likely to have healthcare unaffordability. Unmet healthcare needs were higher in Mexican patients (aOR: 1.43 95%CI: 1.03-1.99) and patients of Cuban descent (aOR: 1.96 95%CI: 1.07-3.58). Financial stress was highest among patients of Central/South American heritage (aOR: 4.20 95%CI: 2.50-7.05) and Mexican patients (aOR: 1.84 95%CI: 1.27-2.66). Mediator analyses further revealed that disparities persisted even after adjusting for socioeconomic status in Mexican patients (healthcare unaffordability - aOR: 1.65 95%CI: 1.14-2.40) and patients of Central/South American heritage (healthcare unaffordability – aOR: 1.99 95%CI: 1.23-3.21; general financial stress – aOR: 2.97 95%CI: 1.71 – 5.17). Conclusions: Our study highlights significant disparities in the financial impact of cancer treatments on Hispanic patients. Disaggregation by Hispanic country of origin illustrates differences within the Hispanic and Hispanic-American population and reveals specific groups that may be at particular risk of financial harm. Targeted interventions to improve health care access and affordability are needed to increase equity and improve outcomes.
DIPG-39. New preclinical models for Diffuse Midline Glioma
Authors: Marbod Klenner, Pia Freidel, Mariella G Filbin, Alexander Beck
Journal: Neuro-Oncology (2022)

Abstract Malignant brain tumors are the leading cause of childhood death in Germany, with Diffuse Midline Glioma (DMG) being the most lethal of all paediatric brain tumors. Current treatment strategies are limited to irradiation which prolongs survival only by a few months. Preclinical studies have identified effective drug candidates, but translation into the clinic remains a major obstacle. It is known that interactions between tumor cells and components of the TME (tumor microenvironment), such as cell to cell contacts between malignant and non-malignant cells or secreted factors, can increase therapy resistance and progression of brain tumors. However, these important factors are not present in most conventional cell culture models for drug testing. Consequently, there is a need for more realistic DMG models to improve the relevance and translational potential of current drug screening. Therefore, the goal of this study was to develop a new DMG model for drug testing, consisting of induced pluripotent stem cell (iPSC) derived human brain cells and patient derived DMG cells to better mimic the complex tumor microenvironment. We co-cultured three-dimensional cerebral organoids with DMG tumor spheres resulting in the formation of DMG-Brain-Organoids (DBO). Preliminary results show that co-culture induces distinct tumor cell subpopulations corresponding to those detected in DMG tumors by single cell RNA sequencing (Filbin et al., 2018). These subpopulations mainly differ in their proliferative capacity and their differential response to clinical interventions may be critical for therapeutic success. DBOs subjected to drug treatments (single or combination) were sectioned and individual therapy effects on tumor cell subpopulations and proliferative capacity were monitored using multiplexed immunofluorescence imaging. By observing drug effects in a realistic setup, we hope to improve the predictive power of our preclinical drug screens and to find new combination therapies for DMG.
Influence of racial and ethnic identity on overall survival in patients with chronic lymphocytic lymphoma.
Authors: Victoria Vardell, Daniel Arthur Ermann, Harsh Shah, Lindsey Fitzgerald, Boyu Hu, Deborah Marie Stephens
Journal: Journal of Clinical Oncology (2022)

7508 Background: Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and results in highly variable clinical outcomes. Epidemiologically, CLL occurs in White ethnicity more frequently and thus, CLL outcomes among underrepresented minorities are not well studied. We sought to examine differences in treatment patterns and survival outcomes based on racial identity of CLL patients and how these have changed over time. Methods: The National Cancer Database was used to identify CLL patients diagnosed from 2004-2018. Demographic and treatment characteristics were compared between White, Black, Asian, Hispanic and other minority groups. Kaplan Meier and adjusted Cox regression survival analysis were used to compare overall survival (OS) between races. Survival analysis was repeated by year of diagnosis in Black and White populations. Results: Of 97,804 CLL pts identified, 90.7% of patients were White, 7.6% Black (N = 7,391), 2.6% Hispanic (N = 2,487), 0.6% Asian (N = 613), and 1.1% were other. Compared to White pts, Black pts were younger at diagnosis (median age 66 years [interquartile range 61-79] vs. 70 years [range 58-75], more likely to have ≥1 comorbidity (27.9% vs. 21.3%), and be uninsured (6.6% vs. 2.1%) (all p &lt; 0.001). Black pts were more likely than White pts to have CLL directed treatment immediately after diagnosis (35.9% vs 23.6%; p &lt; 0.001). With a median follow-up of 4.3 years, median OS for all CLL patients was 9.0 years (CI 8.9-9.1 years). Black pts had a shorter median OS of 7.0 years (CI 6.7-7.3 years) compared to White pts (9.14 years [CI 9.0-9.3]), p &lt; 0.001), as well as inferior OS at 5-years (61% vs. 69%) and 10-years (36% vs. 46%), p &lt; 0.001. On multivariate analysis adjusted for age and Charlson-Deyo score, Black race was independently associated with shorter OS (HR 1.51 [CI 1.46-1.57], p &lt; 0.001). While OS lengthened with successive year of diagnosis for all races, the relative survival of Black compared to White pts did not improve over the observed time period. Referenced to the White population, Black pts diagnosed between 2004-2006 had a HR of 1.64 (CI 1.52-1.76) for mortality, and those diagnosed between 2016-2018 had a HR of 1.64 (CI 1.44-1.85). Conclusions: We present the largest study to date describing racial disparities in CLL. Black pts have significantly shorter OS compared to White pts, which is sustained when adjusted for the higher prevalence of comorbidities in the Black CLL population. Unfortunately, the survival gap between White and Black patients has not improved since 2004, highlighting the need for targeted research directed at improving survival in Black pts with CLL. [Table: see text]
Five- or 10-year colonoscopy for 1-2 non-advanced adenomatous polyps (FORTE) NRG-CC005 study: A randomized phase III non-inferiority trial comparing colorectal cancer incidence in participants with 1-2 non-advanced adenomas randomized to a 5- and 10-year surveillance colonoscopy exam schedule versus a 10-year surveillance colonoscopy exam schedule.
Authors: Robert E Schoen, Hanna Bandos, Douglas Corley, Jeff Dueker, Greg Yothers, Jinbing Bai, Warner King Huh, Julie E. Bauman, Joan L. Walker, Deborah Bruner, Lisa A. Kachnic
Journal: Journal of Clinical Oncology (2022)

TPS3631 Background: Adenomatous polyps are the acknowledged precursors of colorectal cancer (CRC). Identification and removal of adenomas is the mechanism by which screening is effective in reducing CRC incidence and mortality. Patients with 1-2 non-advanced adenomas ( &lt; 1 cm with neither villous components nor high grade dysplasia) are recommended to return at a timing ranging from 5-10 yrs. However, evidence for the benefit, optimal timing, and recommended frequency of surveillance colonoscopy is not available. A randomized, clinical trial to demonstrate the difference in results between 5- or 10-yr surveillance for participants with non-advanced adenoma can guide clinical practice. Methods: NRG-CC005/FORTE is a prospective, randomized, non-blinded, Phase III, non-inferiority clinical trial comparing CRC incidence in participants randomized to recommendation for a 5- and 10-yr vs. a 10-yr only surveillance colonoscopy exam schedule. Other pre-defined exploratory endpoints include incidence of advanced adenomas, CRC mortality, and incidence of stage III-IV CRCs. Stratification factors include age, gender, and time from qualifying colonoscopy to randomization. Participants ≥50 and &lt; 70 yrs of age at the time of randomization with a first-time diagnosis of 1-2 non-advanced tubular adenomas from the qualifying colonoscopy within 4 yrs prior to randomization will be eligible. Participants with a clinical diagnosis of a significant genetic risk for CRC or with a family history of CRC diagnosed at ≤60 yrs in a first degree relative or in two first degree relatives diagnosed at any age are ineligible. Other ineligibility criteria include prior history of CRC or colorectal adenomas, a hyperplastic polyp measuring ≥1 cm or traditional serrated adenomas, or life expectancy &lt; 10 yrs due to comorbid conditions. Collection of blood, stool, and tissue samples is planned. Statistics: The primary endpoint for the trial is CRC incidence. The trial is focused on CRCs diagnosed between year 5 and year 10. By incorporating a window of +/- 1 yr to allow for somewhat earlier and later procedures, as typically occurs in clinical medicine, the primary endpoint will include incident cancers identified in years 4 through 11. A crude 4- to 11-yr incidence rate of 0.387% is assumed for the 5- and 10-yr schedule arm. The study is powered at 90% to detect a non-inferiority margin difference of 0.387% at alpha 5% in CRC incidence rate between two schedules. 9,500 participants are to be enrolled. Support: U10CA180868, -180822, UG1CA189867, U24CA196067 Clinical trial information: NCT05080673.
Hepatocellular Carcinoma: Pick the Winner—Tyrosine Kinase Inhibitor Versus Immuno-oncology Agent–Based Combinations
Authors: Anthony C. Bejjani, Richard S. Finn
Journal: Journal of Clinical Oncology (2022)

The treatment landscape for advanced hepatocellular carcinoma has changed dramatically over the past 4 years. We now have numerous options for patients in frontline, second-line, and beyond. The most significant impact has been the introduction of immunotherapy into our treatment paradigms. We now have regimens that induce consistent double-digit objective response rates and markedly improve overall survival (OS) with favorable side effect profiles. The combination of atezolizumab and bevacizumab has demonstrated that the combination of targeting programmed death-ligand 1 and the vascular endothelial growth factor axis can improve outcomes versus sorafenib in the IMBrave150 study. Results from the COSMIC-312 study evaluating the multikinase vascular endothelial growth factor receptor, hepatocyte growth factor receptor, and AXL tyrosine kinase receptor inhibitor cabozantinib in combination with atezolizumab improved progression-free survival versus sorafenib, but at this time, there is no improvement in OS and response rates were lower than expected. Additional data with similar combinations are awaited on the basis of encouraging early-phase data. In addition, the combination of cytotoxic T-lymphocyte–associated protein 4 and programmed cell death-1/programmed death-ligand 1 targeting is yielding similar promising early results, and the phase III HIMALAYA study met its primary end points of improving OS versus sorafenib for durvalumab plus tremelimumab and demonstrated noninferiority for single-agent durvalumab as well. However, this combination did not improve progression-free survival and objective response rates with this combination did not seem significantly different from that with single-agent durvalumab. Although there are still knowledge gaps in this rapidly changing landscape, we will address some of the important questions relevant to making therapeutic decisions in the management of advanced hepatocellular carcinoma in the modern era on the basis of our current knowledge of the safety and efficacy of these evolving regimens. The goal is to provide clinicians with the knowledge needed to optimize outcomes for their patients.